The mechanism by which beta-adrenergic antagonists lower blood pressure in hypertensive humans has not been established. One hypothesis is that these drugs have an action in the brain which results in a decrease in peripheral sympathetic nerve activity and thereby a drop in total peripheral resistance. A central site of drug action is not easily studied in patients, but can be systematically explored in the spontaneously hypertensive (SH) rat. Wistar-Kyoto (WK) rats will serve as the genetically related normotensive control. The effect with time of single and multiple doses of propranolol, metoprolol and timolol on blood pressure and heart rate in conscious, freely-moving SH and WK rats will be compared with the ability of these drugs to alter the neural release of norepinephrine (NE) and serotonin (5-HT) in ten different regions of the brain at times when blood pressure is beginning to fall or has already decreased. Changes in the amount of NE and 5-HT released in each brain region will be assessed by measuring the concentrations of their major terminal metabolites, 3-methoxy-4-hydroxyphenylethylglycol (MOPEG) and 5-hydroxyindole-3-acetic acid, respectively. During chronic therapy with these drugs, changes in the plasma concentration of NE (released from peripheral neurons) as well as changes in the urinary excretion of MOPEG (completely derived from the metabolism of NE released by the peripheral nervous system) will be assessed. The pharmacokinetic relationship between the concentration of these drugs in the serum and brain, after single and multiple doses, will be determined. The regional distribution of propranolol, metoprolol and timolol in ten different brain areas also will be measured. These studies will provide data which will help to elucidate a central antihypertensive site of action of the beta-adrenergic antagonists and will describe the rate at which these agents enter and leave the brain after single and multiple doses.